This invention relates to heterocyclic derivatives that bind to the benzodiazepine site of GABAA receptors. This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in the treatment of central nervous system (CNS) diseases. This invention also relates to the use of these heterocyclic compounds in combination with one or more other CNS agents to potentiate the effects of the other CNS agents. Additionally this invention relates to the use such compounds as probes for the localization of GABAA receptors in tissue sections.
The GABAA receptor superfamily represents one of the classes of receptors through which the major inhibitory neurotransmitter, xcex3-aminobutyric acid, or GABA, acts. Widely, although unequally, distributed through the mammalian brain, GABA mediates many of its actions through a complex of proteins called the GABAA receptor, which causes alteration in chloride conductance and membrane polarization.
A number of cDNAs for GABAA receptor subunits have been characterized. To date at least 6xcex1, 3xcex2, 3xcex3, 1xcex5, 1xcex4 and 2xcfx80 subunits have been identified. It is generally accepted that native GABAA receptors are typically composed of 2xcex1, 2xcex2, and 1xcex3 subunits (Pritchett and Seeburg Science 1989; 245:1389-1392 and Knight et. al., Recept. Channels 1998; 6:1-18). Evidence such as message distribution, genome localization and biochemical study results suggest that the major naturally occurring receptor combinations are xcex11xcex22xcex32, xcex12xcex23xcex32, xcex13xcex23xcex32, and xcex15xcex23xcex32 (Mohler et. al. Neuroch. Res. 1995; 20(5): 631-636).
Benzodiazepines exert their pharmacological actions by interacting with the benzodiazepine binding sites associated with the GABAA receptor. In addition to the benzodiazepine site, the GABAA receptor contains sites of interaction for several other classes of drugs. These include a steroid binding site, a picrotoxin site, and the barbiturate site. The benzodiazepine site of the GABAA receptor is a distinct site on the receptor complex that does not overlap with the site of interaction for GABA or for other classes of drugs that bind to the receptor (see, e.g., Cooper, et al., The Biochemical Basis of Neuropharmacology, 6th ed., 1991, pp. 145-148, Oxford University Press, New York). Early electrophysiological studies indicated that a major action of the benzodiazepines was enhancement of GABAergic inhibition. Compounds that selectively bind to the benzodiazepine site and enhance the ability of GABA to open GABAA receptor channels are agonists of GABA receptors. Other compounds that interact with the same site but negatively modulate the action of GABA are called inverse agonists. Compounds belonging to a third class bind selectively to the benzodiazepine site and yet have little or no effect on GABA activity, but can block the action of GABAA receptor agonists or inverse agonists that act at this site. These compounds are referred to as antagonists.
The important allosteric modulatory effects of drugs acting at the benzodiazepine site were recognized early and the distribution of activities at different receptor subtypes has been an area of intense pharmacological discovery. Agonists that act at the benzodiazepine site are known to exhibit anxiolytic, sedative, and hypnotic effects, while compounds that act as inverse agonists at this site elicit anxiogenic, cognition enhancing, and proconvulsant effects. While benzodiazepines have a long history of pharmaceutical use as anxiolytics, these compounds often exhibit a number of unwanted side effects. These may include cognitive impairment, sedation, ataxia, potentiation of ethanol effects, and a tendency for tolerance and drug dependence.
GABAA selective ligands may also act to potentiate the effects of other CNS active compounds. For example, there is evidence that selective serotonin reuptake inhibitors (SSRIs) may show greater antidepressant activity when used in combination with GABAA selective ligands than when used alone.
This invention provides heterocyclic derivatives, particularly imidazoquinoline and 1,2,4-triazoloquinoline derivatives, that bind to the benzodiazepine site of the GABAA receptor, including human GABAA receptors. Preferably, these compounds also bind with high affinity to such receptors. More preferably, these compounds bind with high selectivity to such receptors.
The invention provides compounds of Formula I (shown below), and pharmaceutical compositions comprising compounds of Formula 1.
The invention further provides methods of treating patients suffering from CNS disorders with a therapeutically effective amount of a compound of the invention. The patient may be a human or other mammal. Treatment of humans, domesticated companion animals (pets) and livestock animals suffering from CNS disorders with a therapeutically effective amount of a compound of the invention is contemplated by the invention.
In a separate aspect, the invention provides a method of potentiating the actions of other CNS active compounds. This method comprises administering a therapeutically effective amount of a compound of the invention with another CNS active compound.
Additionally this invention provides for the use of the compounds of the invention as probes for the localization of GABAA receptors in tissue samples, in particular, tissue sections.
The invention also provides intermediate compounds that are useful in the preparation of compounds of Formula 1.
A broad aspect of the invention is directed to compounds of Formula 1: 
And the pharmaceutically acceptable salts thereof, wherein:
X represents N or CR1, wherein
R1 is hydrogen, halogen, hydroxy, cyano, nitro, amino, C1-C6 alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, mono or di(C1-C6)alkylamino, or amino(C1-C6)alkyl;
X1 represents N, CH, or C1-C6alkyl;
Y and Z are independently hydrogen, halogen, hydroxy, cyano, nitro, amino, C1-C6 alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, mono or di(C1-C6)alkylamino, or amino(C1-C6)alkyl; or
Y and Z together form an arylene ring or a C3-C8 cycloalkylene ring, each of which is optionally substituted with up to four groups R2 independently chosen at each occurrence from halogen, hydroxy, cyano, nitro, amino, C1-C6 alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, mono or di(C1-C6)alkylamino, and amino(C1-C6) alkyl;
W is aryl or heteroaryl, each of which is optionally substituted with one or more groups RA, wherein each RA is independently
i) halogen, hydroxy, cyano, nitro, amino, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, xe2x80x94SO2NH2, xe2x80x94SO2NH(C1-C8 alkyl), xe2x80x94SO2N(C1-8 alkyl)(C1-C8 alkyl), xe2x80x94NH(C1-C8 alkyl), xe2x80x94N(C1-C8 alkyl) (C1-8 alkyl), xe2x80x94N(C1-C8 alkyl)CO(C1-C8 alkyl), xe2x80x94N(C1-C8 alkyl)CO2(C1-C8 alkyl), xe2x80x94CONH2, xe2x80x94CONH(C1-C8 alkyl), xe2x80x94CON(C1-C8 alkyl) (C1-C8 alkyl), xe2x80x94CO2(C1-C8 alkyl), xe2x80x94S(C1-C8 alkyl), xe2x80x94SO(C1-C8 alkyl), or xe2x80x94SO2(C1-C8 alkyl);
ii) aryl or heteroaryl, each of which is optionally substituted with one or two groups independently selected from halogen, hydroxy, cyano, nitro, amino, C1-C6 alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, mono or di(C1-C6)alkylamino, and amino (C1-C6) alkyl;
iii) C1-C8alkyl, C2-C8alkenyl, C2-C8 alkynyl, C3-C8cycloalkyl, C3-C8cycloalkyl (C1-C3 alkyl), C3-C8cycloalkenyl, each of which is unsubstituted or substituted by one or more substituents independently selected from hydroxy, oxo, halogen, C1-C6alkoxy, xe2x80x94CONH2, xe2x80x94CONHC1-C6alkyl, xe2x80x94CON(C1-C6alkyl) (C1-C6alkyl), xe2x80x94COOH, and xe2x80x94CO2C1-C6alkyl; or
iv) NR4R5, wherein R4, R5 and the nitrogen to which they are attached form a monocyclic or bicyclic ring optionally containing one or more of oxo, O, S, SO, SO2, or NR6 wherein R6 is hydrogen, C1-C6alkyl, or Arxe2x80x94(C1-C6alkyl) where
Ar is aryl or heteroaryl, each of which is optionally substituted by one or two groups independently selected from halogen, hydroxy, cyano, nitro, amino, C1-C6 alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, mono or di(C1-C6)alkylamino, and amino(C1-C6)alkyl; and
Q is selected Formulas III, IV and V: 
xe2x80x83wherein:
J is N or C1-C8 alkylene; and
R9 and R10 are independently hydrogen, C1-C8 alkyl, or Ar1, wherein Ar1 is aryl or heteroaryl, each of which may be substituted with one or two of RB, where each RB independently carries the definition of RA; or
R9, R10 and the atom to which they are attached form a 4-to 8-membered monocyclic or bicyclic ring optionally containing one or more double bonds or one or more of oxo, O, S, SO, SO2, or Nxe2x80x94R8 wherein R8 is hydrogen, C1-C8 alkyl, or Ar1xe2x80x94(C1-C8 alkyl); wherein Ar1 is optionally substituted with one or two of RB, where each RB independently carries the definition of RA; and wherein the monocyclic or bicyclic ring is optionally substituted with C1-C6 alkyl or hydroxy(C1-C6) alkyl;
R11 is selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8 alkanoyl, aryl(C1-C6)alkyl, and aryl(C1-C6) alkanoyl; and
R12 is selected from the group consisting of hydrogen, C1-C8 alkyl, and C1-C8 alkoxy; or
R11 and R12 together with the atoms to which they are attached form a 5-8 membered monocyclic ring which is optionally substituted with one or more of halogen, hydroxy, cyano, nitro, amino, C1-C6 alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, mono or di(C1-C6)alkylamino, or amino(C1-C6)alkyl; and
n is 1, 2, 3, or 4; and
Wxe2x80x2
(i) independently carries the same definition as W;
(ii) represents xe2x80x94OR where R is C1-C8 alkyl or aryl(C1-C6)alkyl; or
(iii) is M5 where M5 is hydroxy, C1-C8 alkyl, aryl(C1-C6)alkyl or xe2x80x94N((C1-C4 alkyl) (C1-C4 alkoxy).
For compounds of Formula I (above) preferred aryl and heteroaryl groups representing the variable W include, but are not limited to the groups W1 defined as follows: W1: phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, benzoimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, tetrazolyl, pyrrolyl, indolyl, pyrazolyl or benzopyrazolyl, each of which is optionally substituted by one or more groups independently chosen at each occurrence from
halogen, hydroxy, cyano, nitro, amino, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, xe2x80x94SO2NH2, xe2x80x94SO2NH(C1-C8 alkyl), xe2x80x94SO2N(C1-8 alkyl) (C1-C8 alkyl), xe2x80x94NH(C1-C8 alkyl), xe2x80x94N(C1-C8 alkyl) (C1-8 alkyl), xe2x80x94N(C1-C8 alkyl)CO(C1-C8 alkyl), xe2x80x94N(C1-C8 alkyl)CO2(C1-C8 alkyl), xe2x80x94CONH2, xe2x80x94CONH(C1-C8 alkyl), xe2x80x94CON(C1-C8 alkyl) (C1-C8 alkyl), xe2x80x94CO2(C1-C8 alkyl), xe2x80x94S(C1-C8 alkyl), xe2x80x94SO(C1-C8 alkyl), xe2x80x94SO2(C1-C8 alkyl), and phenyl.
Especially preferred groups representing the variable W includes the groups W2, wherein W2 represents phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, benzoimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, tetrazolyl, pyrrolyl, indolyl, pyrazolyl or benzopyrazolyl, each of which is optionally substituted by one or more groups independently chosen at each occurrence from
halogen, hydroxy, cyano, nitro, amino, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, xe2x80x94SO2NH2, xe2x80x94SO2NH(C1-C8 alkyl), xe2x80x94SO2N(C1-8 alkyl) (C1-C8 alkyl), xe2x80x94NH(C1-C8 alkyl), xe2x80x94N(C1-C8 alkyl) (C1-8 alkyl), xe2x80x94N(C1-C8 alkyl)CO(C1-C8 alkyl), xe2x80x94N(C1-C8 alkyl)CO2(C1-C8 alkyl), xe2x80x94CONH2, xe2x80x94CONH(C1-C8 alkyl), xe2x80x94CON(C1-C8 alkyl) (C1-C8 alkyl), xe2x80x94CO2(C1-C8 alkyl), xe2x80x94S(C1-C8 alkyl), xe2x80x94SO(C1-C8 alkyl), xe2x80x94SO2(C1-C8 alkyl), and phenyl.
A preferred arylene ring formed by Y and Z is benzo. Particularly preferred benzo rings are unsubstituted or substituted with one, two, or three, more preferably one or two, of R2 where each R2 is the same as or different than every other R2. Preferred benzo substituents are halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94CN, amino, xe2x80x94NH(C1-C6 alkyl), and xe2x80x94N(C1-C6 alkyl)2. Highly preferred benzo substituents are halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, amino, xe2x80x94NH(C1-C6 alkyl), and xe2x80x94N(C1-C6 alkyl)2.
Preferred cycloalkylene rings formed by Y and Z are 5-, 6-, and 7-membered cycloalkylene rings. Particularly preferred are 5-, 6-, and 7-membered cycloalkylene rings are that are unsubstituted or are substituted with one, two, or three, preferably one or two, of R2 where each R2 is the same as or different than every other R2. Preferred cycloalkylene substituents are halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94CN, xe2x80x94SO2NH2, amino, xe2x80x94NH(C1-C6 alkyl), and xe2x80x94N(C1-C6 alkyl)2. Highly preferred cycloalkylene substituents are halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, amino, xe2x80x94NH(C1-C6 alkyl), and xe2x80x94N(C1-C6 alkyl)2.
A preferred group of compounds of the invention includes those represented by Formula A-3
wherein R2, Q, X1, X and W are as defined for Formula I and R2 is independently chosen at each occurrence.
Preferred compounds of Formula A-3 include compounds where
W is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, benzoimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, tetrazolyl, pyrrolyl, indolyl, pyrazolyl or benzopyrazolyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of:
halogen, hydroxy, cyano, nitro, amino, C1-C8alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, xe2x80x94SO2NH2, xe2x80x94SO2NH(C1-C8 alkyl), xe2x80x94SO2N(C1-8 alkyl) (C1-C8 alkyl), xe2x80x94NH(C1-C8 alkyl), xe2x80x94N(C1-C8 alkyl) (C1-8 alkyl), xe2x80x94N(C1-C8 alkyl)CO(C1-C8 alkyl), xe2x80x94N(C1-C8 alkyl)CO2(C1-C8 alkyl), xe2x80x94CONH2, xe2x80x94CONH(C1-C8 alkyl), xe2x80x94CON(C1-C8 alkyl) (C1-C8 alkyl), xe2x80x94CO2(C1-C8 alkyl), xe2x80x94S(C1-C8 alkyl), xe2x80x94SO(C1-C8 alkyl), xe2x80x94SO2(C1-C8 alkyl) and phenyl.
Even more preferred compounds of Formula A-3 include those where
R2 is independently chosen at each occurrence from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, trifluoromethyl and trifluoromethoxy;
Q is selected from the group consisting of Formulas III, IV and V: 
xe2x80x83wherein:
J is N or C1-C8 alkylene; and
R9 and R10 are independently hydrogen, C1-C8 alkyl; or
R9, R10 and the atom to which they are attached form a 4-to 8-membered monocyclic or bicyclic ring, which may contain one or more double bonds or one or more of oxo, O, S, SO, SO2, or Nxe2x80x94R8 wherein R8 is hydrogen, C1-C8 alkyl; wherein the monocyclic or bicyclic ring is optionally substituted with C1-C6 alkyl or hydroxy (C1-C6) alkyl;
R11 is selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8 alkanoyl, aryl(C1-C6)alkyl, and aryl(C1-C6) alkanoyl; and
R12 is selected from the group consisting of hydrogen, C1-C8 alkyl, and C1-C8 alkoxy; or
R11 and R12 together with the atoms to which they are attached form a 5-8 membered monocyclic ring, which is optionally substituted with C1-C6 alkyl; and
n is 1, 2, 3, or 4;
Wxe2x80x2 phenyl, pyridyl, or naphthyl; and
W is phenyl, thienyl, isoxazolyl, or pyridyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, trifluoromethoxy, and hydroxy.
Other preferred compounds of Formula A-3 include compounds where X1 is CR1 and R1 is hydrogen or C1-C6alkyl.
Preferred compounds of Formula A-3 also include compounds wherein X1 is CR1 and R1 is hydrogen or C1-C6alkyl, and W has the definition of W1 or more preferably W has the definition of W2.
Also preferred are compounds of Formula A-3 wherein X1 is CR1 and R1 is hydrogen or C1-C6alkyl;
R2 is independently selected at each occurrence from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, trifluoromethyl and trifluoromethoxy;
Q is selected from the group consisting of Formulas III, IV and V
xe2x80x83wherein:
J is N or C1-C8 alkylene; and
R9 and R10 are independently hydrogen, C1-C8 alkyl; or
R9 R10 and the atom to which they are attached form a 4- to 8-membered monocyclic or bicyclic ring, which may contain one or more double bonds or one or more of oxo, O, S, SO, SO2, or Nxe2x80x94R8 wherein R8 is hydrogen, C1-C8 alkyl; wherein the monocyclic or bicyclic ring is optionally substituted with C1-C6 alkyl or hydroxy(C1-C6)alkyl;
R11 is selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8 alkanoyl, aryl(C1-C6)alkyl, and aryl(C1-C6)alkanoyl; and
R12 is selected from the group consisting of hydrogen, C1-C8 alkyl, and C1-C8 alkoxy; or
R11 and R12 together with the atoms to which they are attached form a 5-8 membered monocyclic ring, which is optionally substituted with C1-C6 alkyl; and
n is 1, 2, 3, or 4;
Wxe2x80x2 phenyl, pyridyl, or naphthyl; and
W is phenyl, thienyl, isoxazolyl, or pyridyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, trifluoromethoxy, and hydroxy.
Preferred W groups of Formula A-3 are those carrying k-2 substituents where k is the number of hydrogen atoms on the aryl or heteroaryl group defined by W. More preferably, the W groups carry k-3 substituents. The most preferred W groups are those carrying 1 or 2 substituents, and those substituents are most preferably hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, trifluoromethoxy, amino or mono- or di(C1-C6) alkylamino.
Another preferred group of compounds of the invention are those depicted by Formula A-6
wherein R2, Q, and X are defined as in Formula I, R2 is independently defined at each occurrence, and W is W1.
More preferred are compounds of Formula A-6 are those where R2, Q, and X are defined as in Formula I, and W is W2.
More preferred are compounds of Formula A-6 include those where
R2 are independently selected at each occurrence from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, trifluoromethyl and trifluoromethoxy;
Q is selected from the group consisting of Formulas III, IV and V: 
xe2x80x83wherein:
J is N or C1-C8 alkylene; and
R9 and R10 are independently hydrogen, C1-C8 alkyl; or
R9, R10 and the atom to which they are attached form a 4- to 8-membered monocyclic or bicyclic ring, which may contain one or more double bonds or one or more of oxo, O, S, SO, SO2, or Nxe2x80x94R8 wherein R8 is hydrogen, C1-C8 alkyl; wherein the monocyclic or bicyclic ring is optionally substituted with C1-C6 alkyl or hydroxy(C1-C6)alkyl;
R11 is selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8 alkanoyl, aryl(C1-C6)alkyl, and aryl(C1-C6)alkanoyl; and
R12 is selected from the group consisting of hydrogen, C1-C8 alkyl, and C1-C8 alkoxy; or
R11 and R12 together with the atoms to which they are attached form a 5-8 membered monocyclic ring, which is optionally substituted with C1-C6alkyl; and
n is 1, 2, 3, or 4;
Wxe2x80x2 phenyl, pyridyl, or naphthyl; and
W is phenyl, thienyl, isoxazolyl, or pyridyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, trifluoromethoxy, and hydroxy.
Preferred W groups of Formula A-6 are those carrying k-2 substituents where k is the number of hydrogen atoms on the aryl or heteroaryl group defined by W. More preferably, the W groups carry k-3 substituents. The most preferred W groups are those carrying 1 or 2 substituents, and those substituents are most preferably hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, trifluoromethoxy, amino or mono- or di(C1-C6)alkylamino.
Another preferred group of compounds of the invention is represented by Formula A-9, i.e., compound where both X and X1 are both CH, 
wherein R1, R2, and Q are as defined as in Formula 1, and W is W1.
More preferred are compounds of Formula A-9 include those wherein R2 and Q are as defined in Formula I, and W is W1.
Most preferred compounds of formula A-9 are those wherein
R2 is independently selected at each occurrence from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, trifluoromethyl and trifluoromethoxy;
Q is selected from the group consisting of Formulas III, IV and V: 
J is N or C1-C8 alkylene; and
R9 and R10 are independently hydrogen, C1-CC8 alkyl; or
R9, R10 and the atom to which they are attached form a 4- to 8-membered monocyclic or bicyclic ring, which may contain one or more double bonds or one or more of oxo, O, S, SO, SO2, or Nxe2x80x94R8 wherein R8 is hydrogen, C1-C8 alkyl; wherein the monocyclic or bicyclic ring is optionally substituted with C1-C6 alkyl or hydroxy(C1-C5 ) alkyl;
R11 is selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8 alkanoyl, aryl(C1-C6)alkyl, and aryl (C1-C6) alkanoyl; and
R12 is selected from the group consisting of hydrogen, C1-C8 alkyl, and C1-C8 alkoxy; or
R11 and R12 together with the atoms to which they are attached form a 5-8 membered monocyclic ring, which is optionally substituted with C1-C6alkyl; and
n is 1, 2, 3, or 4;
Wxe2x80x2 phenyl, pyridyl, or naphthyl; and
W is phenyl, thienyl, isoxazolyl, or pyridyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, trifluoromethoxy, and hydroxy.
Preferred W groups of Formula A-9 are those carrying k-2 substituents where k is the number of hydrogen atoms on the aryl or heteroaryl group defined by W. More preferably, the W groups carry k-3 substituents. The most preferred W groups are those carrying 1 or 2 substituents, and those substituents are most preferably hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, trifluoromethoxy, amino or mono- or di(C1-C6)alkylamino.
Still another preferred group of compounds is represented by Formula A-12. 
wherein
wherein R1, Q, and X are as defined in Formula I and p is 1, 2, 3, and 4; and W is W1.
More preferred compounds of Formula A-12 are those where
R2, Q, and X are as defined in Formula 1;
p is 1, 2, 3, or 4; and
W is W2.
Even more preferred compounds of Formula 12 are those wherein
R2 is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, trifluoromethyl and trifluoromethoxy;
Q is selected from the group consisting of Formulas III, IV and V: 
xe2x80x83wherein:
J is N or C1-C8 alkylene; and
R9 and R10 are independently hydrogen, C1-C8 alkyl; or
R9, R10 and the atom to which they are attached form a 4- to 8-membered monocyclic or bicyclic ring, which may contain one or more double bonds or one or more of oxo, O, S, SO, SO2, or Nxe2x80x94R8 wherein R8 is hydrogen, C1-C8 alkyl; wherein the monocyclic or bicyclic ring is optionally substituted with C1-C6 alkyl or hydroxy(C1-C6)alkyl;
R11 is selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8 alkanoyl, aryl(C1-C6)alkyl, and aryl(C1-C6)alkanoyl; and
R12 is selected from the group consisting of hydrogen, C1-C8 alkyl, and C1-C8 alkoxy; or
R11 and R12 together with the atoms to which they are attached form a 5-8 membered monocyclic ring, which is optionally substituted with C1-C6 alkyl; and
n is 1, 2, 3, or 4;
Wxe2x80x2 phenyl, pyridyl, or naphthyl; and
W is phenyl, thienyl, isoxazolyl, or pyridyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, trifluoromethoxy, and hydroxy.
Preferred compounds of the invention are also encompassed by Formula A-15
wherein R1, Q, and X are as defined in Formula 1; p is 1, 2, 3, or 4; and W is W1.
More compounds of Formula A-15 are those wherein
R2, Q, and X are as defined in Formula 1;
p is 1, 2, or 3; and
W is W2.
Even more preferred compounds of Formula A-15 are those where
R2 is independently selected at each occurrence from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, trifluoromethyl and trifluoromethoxy;
Q is selected from the group consisting of Formulas III, IV and V: 
xe2x80x83wherein:
J is N or C1-C8 alkylene; and
R9 and R10 are independently hydrogen, C1-C8 alkyl; or
R9, R10 and the atom to which they are attached form a 4- to 8-membered monocyclic or bicyclic ring, which may contain one or more double bonds or one or more of oxo, O, S, SO, SO2, or Nxe2x80x94R8 wherein R8 is hydrogen, C1-C8 alkyl; wherein the monocyclic or bicyclic ring is optionally substituted with C1-C6 alkyl or hydroxy(C1-C6 )alkyl;
R11 is selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8 alkanoyl, aryl(C1-C6)alkyl, and aryl(C1-C6)alkanoyl; and
R12 is selected from the group consisting of hydrogen, C1-C8 alkyl, and C1-C8 alkoxy; or
R11 and R12 together with the atoms to which they are attached form a 5-8 membered monocyclic ring, which is optionally substituted with C1-C6 alkyl; and
n is 1, 2, 3, or 4;
Wxe2x80x2 phenyl, pyridyl, or naphthyl; and
W is phenyl, thienyl, isoxazolyl, or pyridyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, trifluoromethoxy, and hydroxy.
Preferred compounds of the invention are also encompassed by Formula A-17, i.e., compounds where Y and Z are not joined to form an aryl ring. 
wherein X, X1, and Q are defined as in Formula I, and W is W1; and
Y and Z are independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C1-C6 alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, mono or di(C1-C6)alkylamino, amino(C1-C6)alkyl.
More preferred compounds of Formula A-17 are those wherein X, X1, and Q are defined as in Formula I, and W is W2; and Y and Z are independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C1-C6 alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, mono or di(C1-C6)alkylamino, amino(C1-C6)alkyl.
Even more preferred are compounds of Formula A-17 wherein
X is N or CH; and
Q is selected from the group consisting of Formulas III, IV and V: 
xe2x80x83wherein:
J is N or C1-C8 alkylene; and
R9 and R10 are independently hydrogen, C1-C8 alkyl; or
R9, R10 and the atom to which they are attached form a 4- to 8-membered monocyclic or bicyclic ring, which may contain one or more double bonds or one or more of oxo, O, S, SO, SO2, or Nxe2x80x94R8 wherein R8 is hydrogen, C1-C8 alkyl; wherein the monocyclic or bicyclic ring is optionally substituted with C1-C6 alkyl or hydroxy(C1-C6)alkyl;
R11 is selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8 alkanoyl, aryl(C1-C6)alkyl, and aryl(C1-C6)alkanoyl; and
R12 is selected from the group consisting of hydrogen, C1-C8 alkyl, and C1-C8 alkoxy; or
R11 and R12 together with the atoms to which they are attached form a 5-8 membered monocyclic ring, which is optionally substituted with C1-C6 alkyl; and
n is 1, 2, 3, or 4;
Wxe2x80x2 phenyl, pyridyl, or naphthyl; and
W is phenyl, thienyl, isoxazolyl, or pyridyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, trifluoromethoxy, and hydroxy.
Other preferred compounds are represented by Formula A-18
W is phenyl, isoxazolyl, thienyl, pyridyl, quinolyl, each of which is optionally substituted with one, two, or three of V1, V2 and V3, where V1, V2, and V3 independently represent halogen, hydroxy, C1-C6 alkyl, C1-C8 alkoxy, xe2x80x94NO2, xe2x80x94CN, amino, xe2x80x94NH(C1-C8 alkyl), or xe2x80x94N(C1-C8 alkyl) (C1-C8 alkyl);
R1 and R2 independently represent hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C8 alkoxy, xe2x80x94NO2, xe2x80x94CN, amino, xe2x80x94NH(C1-C8 alkyl), or xe2x80x94N(C1-C8 alkyl) (C1-C8 alkyl);
X is nitrogen or CR111, where R111 is hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C8 alkoxy, xe2x80x94NO2, xe2x80x94CN, amino, xe2x80x94NH(C1-C8 alkyl), or xe2x80x94N(C1-C8 alkyl) (C1-C8 alkyl); and
R9 and R10 are independently hydrogen or C1-C8 alkyl; or
NR9R10 represents a 5- to 7-membered ring optionally containing one or two double bonds, O and/or Nxe2x80x94R8 where R8 is hydrogen, C1-C8 alkyl, or HArxe2x80x94(C1-C8)alkyl, where HAr is phenyl, pyridinyl, or pyrimidinyl, each of which is optionally substituted with one or two halogen, hydroxy, hydroxy(C1-C6)alkyl, C1-C6 alkyl, C1-C8 alkoxy, xe2x80x94NO2, xe2x80x94CN, amino, xe2x80x94NH(C1-C8 alkyl), or xe2x80x94N(C1-C8 alkyl) (C1-C8 alkyl).
More preferred compounds of Formula A-18 include those where X is nitrogen.
Still other more preferred compounds of Formula A-18 are those where X is CH or a carbon atom substituted with (C1-C6) alkyl.
Other preferred compounds are represented by Formula A-19
W is phenyl, isoxazolyl, thienyl, pyridyl, quinolyl, each of which is optionally substituted with one, two, or three of V1, V2 and V3, where V1, V2, and V3 independently represent halogen, hydroxy, C1-C6 alkyl, C1-C8 alkoxy, xe2x80x94NO2, xe2x80x94CN, amino, xe2x80x94NH(C1-C8 alkyl), or xe2x80x94N(C1-C8 alkyl) (C1-C8 alkyl);
R1 and R2 independently represent hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C8 alkoxy, xe2x80x94NO2, xe2x80x94CN, amino, xe2x80x94NH(C1-C8 alkyl), or xe2x80x94N (C1-C8 alkyl) (C1-C8 alkyl);
X is nitrogen or CR111, where R111 is hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C8 alkoxy, xe2x80x94NO2, xe2x80x94CN, amino, xe2x80x94NH(C1-C8 alkyl), or xe2x80x94N(C1-C8 alkyl) (C1-C8 alkyl); and
Wxe2x80x2 represents
(i) phenyl optionally substituted with one, two, or three of T1, T2 and T3, where T1, T2, and T3 independently represent halogen, hydroxy, C1-C6 alkyl, C1-C8 alkoxy, xe2x80x94NO2, xe2x80x94CN, amino, xe2x80x94NH(C1-C8 alkyl), or xe2x80x94N(C1-C8 alkyl) (C1-C8 alkyl);
(ii) xe2x80x94OR where R is C1-C8 alkyl or aryl(C1-C6)alkyl; or
(iii) M5 where M5 is hydroxy, C1-C8 alkyl, aryl(C1-C6)alkyl or xe2x80x94N(C1-C4 alkyl) (C1-C4 alkoxy).
More preferred compounds of Formula A-19 include those where X is nitrogen.
Still other more preferred compounds of Formula A-19 are those where X is CH or a carbon atom substituted with (C1-C6) alkyl.
Still other preferred compounds are represented by Formula A-20
wherein and Q are as defined in Formula I, and W is W1; and
Y and Z are independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C1-C6 alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, mono or di(C1-C6)alkylamino, amino(C1-C6)alkyl.
Especially preferred definitiona of Y and Z for Formula A-20, are hydrogen, halogen, and C1-C6alkyl. More preferred compounds of Formula A-20, are those where W is W2.
Particularly preferred compounds of Formula A-20 are those wherein
Y and Z are independently chosen from hydrogen, halogen, and C1-C6alkyl, W is W2; and
Q is selected from the group consisting of Formulas III, IV and V: 
xe2x80x83wherein:
J is N or C1-C8 alkylene; and
R9 and R10 are independently hydrogen, C1-C8 alkyl; or
R9, R10 and the atom to which they are attached form a 4- to 8-membered monocyclic or bicyclic ring, which may contain one or more double bonds or one or more of oxo, O, S, SO, SO2, or Nxe2x80x94R8 wherein R8 is hydrogen, C1-C8 alkyl; wherein the monocyclic or bicyclic ring is optionally substituted with C1-C, alkyl or hydroxy(C1-C6)alkyl;
R11 is selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8 alkanoyl, aryl(C1-C6)alkyl, and aryl(C1-C6)alkanoyl; and
R12 is selected from the group consisting of hydrogen, C1-C8 alkyl, and C1-C6 alkoxy; or
R11 and R12 together with the atoms to which they are attached form a 5-8 membered monocyclic ring, which is optionally substituted with C1-C6 alkyl; and
n is 1, 2, 3, or 4;
Wxe2x80x2 phenyl, pyridyl, or naphthyl; and
W is phenyl, thienyl, isoxazolyl, or pyridyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, trifluoromethoxy, and hydroxy.
For Formulas III, IV, and V 
Preferred R8 substituents on the hetero nitrogen (which is sometime present in the 4- to 8-membered monocyclic or bicyclic ring formed by R9 and R10) are methyl, ethyl, n-propyl and isopropyl.
Preferred JR9R10 groups include 1-piperidinyl optionally mono- or disubstituted with C1-C6 alkyl, preferably methyl or ethyl; 1-piperazinyl optionally mono- or disubstituted with C1-C6 alkyl, preferably methyl or ethyl; and morpholinyl optionally mono- or disubstituted with C1-C6 alkyl, preferably methyl or ethyl. Other preferred JR9R10 groups include pyrrolyl and imidazolinyl, each of which is optionally mono- or disubstituted with C1-C3 alkyl or hydroxy (C1-C6) alkyl, and preferably monosubstituted with methyl, ethyl, or hydroxymethyl.
Where the nature of the substituents permits, the groups represented by JR9R10 encompass various stereoisomers. While the invention encompasses racemic mixtures and mixtures of enantiomers in which one enantiomer is present in an enantiomeric excess, the preferred compounds of the invention are those where only a single, at least relatively pure, stereoisomer is present. Examples of preferred JR9R10 stereoisomers include the following: 
As used herein, monocyclic and bicyclic rings include both carbocyclic rings where J is, e.g., CH, and, for those rings formed by NR4R5 and NR4R10, nitrogen-containing carbocyclic ring systems of the type having at least one nitrogen, e.g., the nitrogen in NR4R5. Thus, in NR4R5 and NR9R10, the R4R5 and R9R10 groups together represent, for example, a C4-C6 straight chain alkylene group which together with the nitrogen atom to which, e.g., R9 and R10 are attached form a 5- to 7-membered ring system. This ring system may be further substituted with, e.g., C1-C6 alkyl or may contain one or two double bonds, O, and/or a substituted nitrogen as defined herein. In situations where J is, for example, CH, the resulting ring can contain hetero atoms such as oxygen or nitrogen giving rise to, e.g., a 4-piperidinyl group.
When J is a C1-C8 alkylene group, that group is attached at one terminus to the parent carbonyl and the groups R9 and R10 are attached at any position along the alkylene chain. For example, JR9R10 represents groups such as neopentyl, t-butyl, isopropyl, 2-ethylhexyl and n-octyl. Further, R9R10 may represent an alkylene group, e.g., a C5 alkylene group attached to the terminus of J where is n-propyl giving rise to a cyclohexylpropyl group.
Particularly preferred compounds of Formulas A-3, A-6, and A-9, A-12, A-15, A-17, and A-20 are those where Q represents either Formula III or Formula IV. In highly preferred embodiments, Q represents Formula III where
R9, R10 and the nitrogen atom to which they are attached represent mono- or di(C1-C6)alkylamino; or
R9, R10 and the nitrogen to which they are attached form a 5- or 6-membered ring.
The 5- and 6-membered rings are optionally substituted with C1-C6 alkyl or hydroxy(C1-C6)alkyl, preferably hydroxymethyl, and optionally contain one hetero atom selected from oxygen, sulfur, or nitrogen. The hetero sulfur atom may be oxidized to a sulfone or sulfoxide. The hetero nitrogen is optionally substituted with R8 where R8 represents hydrogen or C1-C8 alkyl.
Other particularly preferred compounds of the invention are those where W represents optionally substituted phenyl, isoxazolyl, or thienyl. Highly preferred compounds are those where the phenyl is unsubstituted or substituted with one or two of halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, trifluoromethoxy, or hydroxy. Other highly preferred compounds are those where W is isoxazolyl optionally substituted with C1-C6 alkyl, most preferably methyl, C1-C6 alkoxy, or halogen. The most preferred compounds are those where W is phenyl optionally substituted with one halogen, preferably chloro or fluoro, or one hydroxy. Even more preferably, the halogen or hydroxy group is in the ortho or para position of the phenyl ring.
The invention also provides intermediates of Formula A-69
wherein Y, Z, and X1 are defined as for Formula I, R is C1-C6alkyl, and RN is hydrogen, C1-C6 alkyl, or xe2x80x94C(O)W where W is as defined for Formula I.
Preferred intermediate compounds can be represented by Formula A-70
wherein X1 and R2 are as defined for Formula I, and R and RN are as defined in Formula A-69.
Another preferred class of intermediates is represented by Formula A-71
wherein X1, Y, and Z are defined as in Formula I, R is C1-C6alkyl and
W is phenyl, pyridyl, isoxazolyl, or thienyl, each of which is unsubstituted or substituted with one or more of halogen, hydroxy, cyano, nitro, amino, C1-C8alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, xe2x80x94SO2NH2, xe2x80x94SO2NH(C1-C8 alkyl), xe2x80x94SO2N(C1-8 alkyl) (C1-C8 alkyl), xe2x80x94NH(C1-C8 alkyl), xe2x80x94N(C1-C8 alkyl) (C8 alkyl), xe2x80x94N(C1-C8 alkyl)CO(C1-C8 alkyl), xe2x80x94N(C1-C8 alkyl)CO2((C1-C8 alkyl), xe2x80x94CONH2, xe2x80x94CONH(C1-C8 alkyl), xe2x80x94CON(C1-C8 alkyl) (C1-C8 alkyl), xe2x80x94CO2(C1-C8 alkyl), xe2x80x94S(C1-C8 alkyl), xe2x80x94SO(C1-C8 alkyl), xe2x80x94SO2(C1-C8 alkyl) and phenyl.
More preferred are intermediate compounds of Formula A-72
wherein X1 and R2 are as defined in Formula I, R is C1-C6alkyl, and W represents W2.
Even more preferred are intermediates of Formula A-73 wherein
R2, is independently selected at each occurrence from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, trifluoromethyl and trifluoromethoxy;
W is W2; and
X1 is N or CH.
Another group of intermediate compounds useful in preparing compounds of the instant invention are those of Formula A-74
wherein Y, Z, X1, and W are as defined for Formula I, and R is C1-C6 alkyl.
More preferred intermediate compounds are represented by formula A-75
wherein X and R2 are as defined in Formula I, R2 is independently chosen at each occurrence, W is W2, and R is C1-C6alkyl.
Even more preferred are intermediates of Formula A-75 wherein
R2 is independently selected at each occurrence from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, trifluoromethyl and trifluoromethoxy;
W is W2; and
X is N or CR1; wherein R1 is selected from the group consisting of hydrogen, halogen, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy.
Still another group of intermediates that are useful in preparing compounds of the instant invention are those of Formula A-76
wherein Y, Z, X, X1, and W are as defined for Formula I, and M5 is hydroxy, C1-C8alkyl, aryl(C1-C6)alkyl, or xe2x80x94N(C1-C4alkyl) (C1-C4alkoxy).
A more preferred group of intermediates of Formula A-76 are those of Formula A-77
wherein X1, R2 and M5 are as defined for formula 76; and W is W2.
A preferred group of intermediates of Formula A-77 are those wherein
R2 is independently selected at each occurrence from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, trifluoromethyl and trifluoromethoxy;
W is W2; and
X1 is N or CH.
This invention relates to imidazoquinoline and triazoloquinoline derivatives and related compounds, preferred examples of which bind with high affinity to the benzodiazepine site of GABAA receptors, including human GABAA receptors. Preferred fused aryl substituted tetrahydroindazoles and related compounds that bind with high selectivity to the benzodiazepine site of GABAA receptors, including human GABAA receptors, are also included in this invention. Without wishing to be bound to any particular theory, it is believed that the interaction of the compounds of Formula I with the benzodiazepine site results in the pharmaceutical utility of these compounds.
The invention further comprises methods of treating patients in need of such treatment with an amount of a compound of the invention sufficient to alter the symptoms of a CNS disorder. Compounds of the inventions that act as agonists at xcex12xcex23xcex32 and xcex13xcex23xcex32 receptor subtypes are useful in treating anxiety disorders such as panic disorder, obsessive compulsive disorder and generalized anxiety disorder; stress disorders including post-traumatic stress, and acute stress disorders. Compounds of the inventions that act as agonists at xcex12xcex23xcex32 and xcex13xcex23xcex32 receptor subtypes are also useful in treating depressive or bipolar disorders and in treating sleep disorders. Compounds of the invention that act as inverse agonists at the xcex15xcex23xcex32 receptor subtype or xcex11xcex22xcex32 and xcex15xcex23xcex32 receptor subtypes are useful in treating cognitive disorders including those resulting from Down Syndrome, neurodegenerative diseases such as Alzheimer""s disease and Parkinson""s disease, and stroke related dementia. Compounds of the invention that act as agonists at the xcex11xcex22xcex32 receptor subtype are useful in treating convulsive disorders such as epilepsy. Compounds that act as antagonists at the benzodiazepine site are useful in reversing the effect of benzodiazepine overdose and in treating drug and alcohol addiction.
The diseases and/or disorders that can also be treated using compounds and compositions according to the invention include:
Depression, e.g. depression, atypical depression, bipolar disorder, depressed phase of bipolar disorder.
Anxiety, e.g. general anxiety disorder (GAD), agoraphobia, panic disorder +/xe2x88x92 agoraphobia, social phobia, specific phobia, Post traumatic stress disorder, obsessive compulsive disorder (OCD), dysthymia, adjustment disorders with disturbance of mood and anxiety, separation anxiety disorder, anticipatory anxiety acute stress disorder, adjustment disorders, cyclothymia.
Sleep disorders, e.g. sleep disorders including primary insomnia, circadian rhythm sleep disorder, dyssomnia NOS, parasomnias, including nightmare disorder, sleep terror disorder, sleep disorders secondary to depression and/or anxiety or other mental disorders, substance induced sleep disorder.
Cognition Impairment, e.g. cognition impairment, Alzheimer""s disease, Parkinson""s disease, mild cognitive impairment (MCI), age-related cognitive decline (ARCD), stroke, traumatic brain injury, AIDS associated dementia, and dementia associated with depression, anxiety or psychosis.
Attention Deficit Disorder, e.g. attention deficit disorder (ADD), and attention deficit and hyperactivity disorder (ADHD).
The invention also provides pharmaceutical compositions comprising compounds of the invention, including packaged pharmaceutical compositions for treating disorders responsive to GABAA receptor modulation, e.g., treatment of anxiety, depression, sleep disorders or cognitive impairment by GABAA receptor modulation. The packaged pharmaceutical compositions include a container holding a therapeutically effective amount of at least one GABAA receptor modulator as described supra and instructions (e.g., labeling) indicating the contained GABAA receptor ligand is to be used for treating a disorder responsive to GABAA receptor modulation in the patient.
In a separate aspect, the invention provides a method of potentiating the actions of other CNS active compounds, which comprises administering an effective amount of a compound of the invention in combination with another CNS active compound. Such CNS active compounds include, but are not limited to the following: for anxiety, serotonin receptor (e.g. 5-HT1A) agonists and antagonists; for anxiety and depression, neurokinin receptor antagonists or corticotropin releasing factor receptor (CRF1) antagonists; for sleep disorders, melatonin receptor agonists; and for neurodegenerative disorders, such as Alzheimer, s dementia, nicotinic agonists, muscarinic agents, acetylcholinesterase inhibitors and dopamine receptor agonists. Particularly the invention provides a method of potentiating the antidepressant activity of selective serotonin reuptake inhibitors (SSRIs) by administering an effective amount of a GABA agonist compound of the invention in combination with an SSRI.
Combination administration can be carried out in a fashion analogous to that disclosed in Da-Rocha, et al. , J. Psychopharmacology (1997) 11(3) 211-218; Smith, et al., Am. J. Psychiatry (1998) 155(10) 1339-45; or Le, et al., Alcohol and Alcoholism (1996) 31 Suppl. 127-132. Also see, the discussion of the use of the GABAA receptor ligand 3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl) methyloxy-1,2,4-triazolo[3,4-a]phthalzine in combination with nicotinic agonists, muscarinic agonists, and acetylcholinesterase inhibitors, in PCT International publications Nos. WO 99/47142, WO 99/47171, and WO 99/47131, respectively. Also see in this regard PCT International publication No. WO 99/37303 for its discussion of the use of a class of GABAA receptor ligands, 1,2,4-triazolo[4,3-b]pyridazines, in combination with SSRIs.
The present invention also pertains to methods of inhibiting the binding of benzodiazepine compounds, such as Ro15-1788, to the GABAA receptors which methods involve contacting a compound of the invention with cells expressing GABAA receptors, wherein the compound is present at a concentration sufficient to inhibit benzodiazepine binding to GABAA receptors in vitro. This method includes inhibiting the binding of benzodiazepine compounds to GABAA receptors in vivo, e.g., in a patient given an amount of a compound of Formula I that would be sufficient to inhibit the binding of benzodiazepine compounds to GABAA receptors in vitro. In one embodiment, such methods are useful in treating benzodiazepine drug overdose. The amount of a compound that would be sufficient to inhibit the binding of a benzodiazepine compound to the GABAA receptor may be readily determined via an GABAA receptor binding assay, such as the assay described in Example 50. The GABAA receptors used to determine in vitro binding may be obtained from a variety of sources, for example from preparations of rat cortex or from cells expressing cloned human GABAA receptors.
The present invention also pertains to methods for altering the signal-transducing activity, particularly the chloride ion conductance of GABAA receptors, said method comprising exposing cells expressing such receptors to an effective amount of a compound of the invention. This method includes altering the signal-transducing activity of GABAA receptors in vivo, e.g., in a patient given an amount of a compound of Formula I that would be sufficient to alter the signal-transducing activity of GABAA receptors in vitro. The amount of a compound that would be sufficient to alter the signal-transducing activity of GABAA receptors may be determined via a GABAA receptor signal transduction assay, such as the assay described in Example 51.
The GABAA receptor ligands provided by this invention and labeled derivatives thereof are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the GABAA receptor.
Labeled derivatives the GABAA receptor ligands provided by this invention are also useful as radiotracers for positron emission tomography (PET) imaging or for single photon emission computerized tomography (SPECT).
If the compounds of the present invention have asymmetric centers, then this invention includes all of the optical isomers and mixtures thereof.
In addition, compounds with carbon-carbon double bonds may occur in Z- and E-forms, with all isomeric forms of the compounds being included in the present invention.
Compounds of Formula I may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be present as, for example, racemic mixtures, mixtures of diastereomers, and optically active forms including mixtures having one stereoisomer in enantiomeric excess and essentially pure stereoisomers, i.e., individual stereoisomers. In these latter situations, the single enantiomers can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column.
Representative compounds of the present invention, which are encompassed by Formula I, include, but are not limited to the compounds in Table I and their pharmaceutically acceptable acid addition salts. In addition, if the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
Non-toxic pharmaceutically acceptable salts include, but are not limited to salts of inorganic acids such as hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic, and nitric or salts of organic acids such as formic, citric, malonic, maleic, fumaric, tartaric, succinic, acetic, lactic, methanesulfonic, p-toluenesulfonic, 2-hydroxyethylsulfonic, salicylic and stearic. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.
The present invention also encompasses the acylated prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I.
When any variable (e.g. C1-C6 alkyl, C1-C8 alkyl, R1-R8, W, X, Ar, G or Q) occurs more than one time in any formula herein, its definition on each occurrence is independent of its definition at every other occurrence.
As used herein, the term xe2x80x9calkylxe2x80x9d includes those alkyl groups of a designed number of carbon atoms. Alkyl groups may be straight, or branched. Examples of xe2x80x9calkylxe2x80x9d include methyl, ethyl, propyl, isopropyl, butyl, iso-, sec- and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl, and the like. Where the number of carbon atoms in the alkyl group is unspecified, the group is a C1-C6 alkyl groups.
The term xe2x80x9calkoxyxe2x80x9d represents an alkyl group of indicated number of carbon atoms attached to the parent molecular moiety through an oxygen bridge. Examples of alkoxy groups include, for example, methoxy, ethoxy, propoxy and isopropoxy. Where the number of carbon atoms in the alkoxy group is unspecified the group is C1-C6 alkoxy.
The term xe2x80x9carylxe2x80x9d refers to an aromatic hydrocarbon ring system containing at least one aromatic ring. The aromatic ring may optionally be fused or otherwise attached to other aromatic hydrocarbon rings or non-aromatic hydrocarbon rings. Examples of aryl groups include, for example, phenyl, naphthyl, anthryl, phenanthryl, 1,2,3,4-tetrahydronaphthyl and biphenyl. Preferred examples of aryl groups include phenyl and naphthyl.
The terms xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d indicate fluorine, chlorine, bromine, and iodine. Preferred halo groups are fluoro, chloro, and bromo. Most preferred are fluoro and chloro.
The term xe2x80x9cheterocycloalkylxe2x80x9d refers to a non-aromatic ring system containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. The heterocycloalkyl ring may be optionally fused to or otherwise attached to other heterocycloalkyl rings and/or non-aromatic hydrocarbon rings. Preferred heterocycloalkyl groups have from 3 to 7 members. Examples of heterocycloalkyl groups include, for example, piperazine, morpholine, piperidine, tetrahydrofuran, pyrrolidine, and pyrazole. Preferred heterocycloalkyl groups include piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-thiomorpholinyl, and pyrolidinyl.
The term xe2x80x9cheteroarylxe2x80x9d refers to an aromatic ring system containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. The heteroaryl ring may be fused or otherwise attached to one or more heteroaryl rings, aromatic or non-aromatic hydrocarbon rings or heterocycloalkyl rings. Examples of heteroaryl groups include, for example, pyridine, furan, thiophene, 5,6,7,8-tetrahydroisoquinoline and pyrimidine. Preferred examples of heteroaryl groups include thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, tetrazolyl, pyrrolyl, indolyl, pyrazolyl, and benzopyrazolyl.
The term xe2x80x9chydroxyalkylxe2x80x9d as used herein, refers to a hydroxy group, attached to the parent molecular moiety through an alkyl group, as defined above.
As used herein, the term xe2x80x9coxoxe2x80x9d refers to a doubly bonded oxygen atom forming carbonyl group with the carbon atom to which the oxygen is attached. Thus, where a ring contains one or more oxo groups, it is intended that that ring contains a carbonyl group in at least one of the ring positions.
This invention relates to heterocyclic derivatives that bind to the benzodiazepine site of GABAA receptors, including human GABAA receptors. A compound may bind to such sites with high affinity but not high specificity or a compound may bind with high selectivity but not high affinity.
The present invention also encompasses the prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies that may be employed to prepare non-toxic pharmaceutically acceptable prodrugs of the compounds encompassed by Formula I. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable solvates, such as water, ethanol, mineral oil, vegetable oil, and dimethylsulfoxide.
The compounds of general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes percutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal injection or infusion techniques and the like. In addition, there is provided a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier. One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants, and if desired other active ingredients. The pharmaceutical compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservative agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques. In some cases such coatings may be prepared by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents or suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil or a mineral oil or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, glucose or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of general Formula I may also be administered in the form of suppositories, e.g., for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.
Compounds of general Formula I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
For administration to non-human animals, the composition may also be added to the animal feed or drinking water. It may be convenient to formulate the animal feed and drinking water compositions so that the animal takes in a therapeutically appropriate quantity of the composition along with its diet. It may also be convenient to present the composition as a premix for addition to the feed or drinking water.
Representative illustrations of the preparation of compounds of Formula 1 in the present invention are given in Schemes 1-3. 
In Scheme I, W, X1, X, and Y are as defined above for Formula 1 and R is C1-C6alkyl, MeOH is methanol, EtOAc is ethyl acetate, DMF is N,N-dimethylformamide, POCl3 is phosphorus oxychloride, and conc. is concentrated. Heat, as used herein, means elevated temperature, such as, for example, about 40 to about 250xc2x0 C. 
In Scheme 2, X, X1, Y, Z, W, Wxe2x80x2, J, R9 and R10 are as defined above for Formula 1, MeOH is methanol, BOP is benzotriazol-1-yloxytris(dimethylamino)-phosphoniumhexafluorophosphate, TEA is triethylamine, DMF is N,N-dimethylformamide, THF is tetrahydrofuran. Heat, as used herein, means elevated temperature, such as, for example, about 40 to about 250xc2x0 C. 
In Scheme 3, X1, Y, Z, W, X, n, R11 and R12 are as defined above for Formula 1, Me is methyl, Tol is toluene and heat as used herein, means elevated temperature, such as, for example, about 40 to about 250xc2x0 C.
Those skilled in the art will recognize that it may be necessary to utilize different solvents or reagents to achieve some of the above transformations.